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Article: Binding of ruthenium and osmium at non‑iron sites of transferrin accounts for their iron-independent cellular uptake

TitleBinding of ruthenium and osmium at non‑iron sites of transferrin accounts for their iron-independent cellular uptake
Authors
KeywordsIron transport
Osmium
Protein surface
Ruthenium
Transferrin
X-ray diffraction
Issue Date2022
Citation
Journal of Inorganic Biochemistry, 2022, v. 234, article no. 111885 How to Cite?
AbstractBeing identified with less toxic and generally showing selective effects for solid tumor metastases, ruthenium and osmium compounds are promising drug candidates for clinical uses. Human serum proteins, such as albumin and transferrin, play vital roles in the transportation and accumulation of ruthenium and osmium agents into target tissues. However, the molecular mechanism of how transferrin transport ruthenium and their osmium analogues at atomic level remains obscure. In this study, we uncovered that the cellular uptake of Os3+ or Ru3+ are not competed by Fe3+. To unveil the molecular mechanism behind the phenomena, we report the first crystal structures of human serum transferrin (hTF) in complex with ruthenium and osmium compounds bound to the non-conserved residues on the surface of hTF without altering its overall conformation. As for Ru3+ and Os3+, these binding sites by descending affinity are: His14/His289, His349–350 ~ His578/Arg581. Ruthenium drugs and their osmium analogues preferentially bind to His14/His289 with bipyridine or imidazole ligands leaving. These binding sites on hTF surface are also available in human lactoferrin and some transferrin family member of other species. The presence of these binding sites makes the cellular uptake of Ru3+ and Os3+ less affected by Fe3+, compare to Zr4+ or Hf4+. Collectively, these findings are critical for our understanding of the role of serum transferrin in cellular delivery of ruthenium and osmium anticancer agents.
Persistent Identifierhttp://hdl.handle.net/10722/319014
ISSN
2023 Impact Factor: 3.8
2023 SCImago Journal Rankings: 0.614
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWang, Minji-
dc.contributor.authorWang, Haibo-
dc.contributor.authorXu, Xiaohan-
dc.contributor.authorLai, Tsz Pui-
dc.contributor.authorZhou, Ying-
dc.contributor.authorHao, Quan-
dc.contributor.authorLi, Hongyan-
dc.contributor.authorSun, Hongzhe-
dc.date.accessioned2022-10-11T12:25:04Z-
dc.date.available2022-10-11T12:25:04Z-
dc.date.issued2022-
dc.identifier.citationJournal of Inorganic Biochemistry, 2022, v. 234, article no. 111885-
dc.identifier.issn0162-0134-
dc.identifier.urihttp://hdl.handle.net/10722/319014-
dc.description.abstractBeing identified with less toxic and generally showing selective effects for solid tumor metastases, ruthenium and osmium compounds are promising drug candidates for clinical uses. Human serum proteins, such as albumin and transferrin, play vital roles in the transportation and accumulation of ruthenium and osmium agents into target tissues. However, the molecular mechanism of how transferrin transport ruthenium and their osmium analogues at atomic level remains obscure. In this study, we uncovered that the cellular uptake of Os3+ or Ru3+ are not competed by Fe3+. To unveil the molecular mechanism behind the phenomena, we report the first crystal structures of human serum transferrin (hTF) in complex with ruthenium and osmium compounds bound to the non-conserved residues on the surface of hTF without altering its overall conformation. As for Ru3+ and Os3+, these binding sites by descending affinity are: His14/His289, His349–350 ~ His578/Arg581. Ruthenium drugs and their osmium analogues preferentially bind to His14/His289 with bipyridine or imidazole ligands leaving. These binding sites on hTF surface are also available in human lactoferrin and some transferrin family member of other species. The presence of these binding sites makes the cellular uptake of Ru3+ and Os3+ less affected by Fe3+, compare to Zr4+ or Hf4+. Collectively, these findings are critical for our understanding of the role of serum transferrin in cellular delivery of ruthenium and osmium anticancer agents.-
dc.languageeng-
dc.relation.ispartofJournal of Inorganic Biochemistry-
dc.subjectIron transport-
dc.subjectOsmium-
dc.subjectProtein surface-
dc.subjectRuthenium-
dc.subjectTransferrin-
dc.subjectX-ray diffraction-
dc.titleBinding of ruthenium and osmium at non‑iron sites of transferrin accounts for their iron-independent cellular uptake-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jinorgbio.2022.111885-
dc.identifier.pmid35690040-
dc.identifier.scopuseid_2-s2.0-85131454873-
dc.identifier.volume234-
dc.identifier.spagearticle no. 111885-
dc.identifier.epagearticle no. 111885-
dc.identifier.eissn1873-3344-
dc.identifier.isiWOS:000816165700003-

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